Controversial Klotho in cancer

The soluble protein Klotho was initially widely believed to be an anti-aging factor: knockout mice live short lives and display symptoms of segmental progeria, and increasing klotho gene dosage protects the kidneys against age-related decline. Mechanistic studies suggested that loss-of-function mutations in klothoderepress the Wnt signaling pathway, resulting in premature cellular senescence.

More recently, however, the relationship between Klotho and bona fide aging has been called into question — specifically by the claim that klotho mutants are suffering from hypervitaminosis D. While this syndrome can phenocopy some aspects of aging (so the argument goes) it does not represent premature aging as such: the klotho mutant phenotype can be partially rescued by placing mice on a diet low in vitamin D, a regimen that does nothing to slow normal aging. This has led some to argue that Klotho should no longer be considered a pro-longevity factor.

The tennis match continues, most recently with a forceful volley from the pro-“klotho as anti-aging gene” side of the court. Wolf et al. remind us that Klotho downregulates the IGF-I signaling pathway (in which loss-of-function mutation generally extends lifespan; this is consistent with a bona fide anti-aging role for Klotho), and describe the gene’s effects on the proliferation of breast cancer cell lines:

Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer

Klotho is an anti-aging gene, which has been shown to inhibit the insulin and insulin-like growth factor 1 (IGF-1) pathways in mice hepatocytes and myocytes. As IGF-1 and insulin regulate proliferation, survival and metastasis of breast cancer, we studied klotho expression and activities in human breast cancer. Immunohistochemistry analysis of klotho expression in breast tissue arrays revealed high klotho expression in normal breast samples, but very low expression in breast cancer. In cancer samples, high klotho expression was associated with smaller tumor size and reduced KI67 staining. Forced expression of klotho reduced proliferation of MCF-7 and MDA-MB-231 breast cancer cells, whereas klotho silencing in MCF-7 cells, which normally express klotho, enhanced proliferation. Moreover, forced expression of klotho in these cells, or treatment with soluble klotho, inhibited the activation of IGF-1 and insulin pathways, and induced upregulation of the transcription factor CCAAT/enhancer-binding protein beta, a breast cancer growth inhibitor that is negatively regulated by the IGF-1-AKT axis. Co-immunoprecipitation revealed an interaction between klotho and the IGF-1 receptor. Klotho is also a known modulator of the fibroblast growth factor (FGF) pathway, a pathway that inhibits proliferation of breast cancer cells. Studies in breast cancer cells revealed increased activation of the FGF pathway by basic FGF following klotho overexpression. Klotho did not affect activation of the epidermal growth factor pathway in breast cancer cells. These data suggest klotho as a potential tumor suppressor and identify it as an inhibitor of the IGF-1 pathway and activator of the FGF pathway in human breast cancer.

In summary, then: As in other systems, Klotho downregulates the IGF-1 pathway in breast cancer (from the co-IPs, it looks like it might be acting as a receptor antagonist). Systemic downregulation of the IGF-1 pathway results in lifespan extension; here, it appears to slow proliferation of two cultured breast cancer cell lines with rather different behavioral profiles (MB-231 is quite aggressive, whereas MCF-7 is more genteel). From the tissue arrays, the Klotho expression pattern behaves as one would expect for a tumor suppressor: high in normal breast tissue but low in tumor cells; within tumors, higher Klotho correlates with endpoints associated with better outcomes (smaller tumors and lower levels of proliferation markers).

Within the larger context of the Klotho controversy, this study is a staunch argument in favor of continued study of the gene as an anti-tumor and anti-aging factor: in this system at least, Klotho is slowing tumor growth and inactivating a gerontogene. ( Let us take as read the somewhat bitchy criticism that most of the main results are from cell culture, and that it would be nice to see confirmation in whole-organism studies.) Thus, the results deal a strong blow against the claim that the Klotho phenotypes are an epiphenomenon resulting from a derangement of vitamin metabolism. After all, one can’t cure cancer by withholding vitamin D.

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4 Responses to “Controversial Klotho in cancer”

Even weirder, vitamin D can mediate apoptosis (http://www.jbc.org/cgi/content/abstract/276/12/9101). Since Klotho inhibits 1,25-dihydroxy vitamin D production, you would think that higher Klotho would, by taking away an apoptotic pathway, exacerbate the uncontrolled growth in cancer. The Wolf et al. results seem to indicate that Klotho’s IGF antagonism is a more important effect in regards to cell proliferation than its inhibition of vitamin D synthesis.
I suppose that if the cells used did not express the enzyme responsible for 1,25 dihydroxy vitamin D, then this result would make sense (sorry, being a bitch :)).

CONTRARY to what is expected, many studies have come to the conclusion that vitamin D concentrations are generally higher among people in northern Europe than among people in southern Europe [30], [31]. Our average serum 25-hydroxyvitamin D levels are in line with the earlier Swedish values estimated in the MORE study [30]. These values were, independent of season, approximately 30% higher than the average among people from central and southern Europe. The results have been explained by a diet containing more vitamin D-fortified foods, lighter skin and wearing lighter clothing when being outdoors during the summer [30], [31]. Our results indicate that our genes, as well as environmental factors, contribute to our vitamin D status. Higher vitamin D concentrations in northern countries may have a genetic basis.”

For a given amount of sun whites will have higher levels of vitamin D than blacks for genetic reasons, in fact they have higher levels for the same exposure than even southern Europeans. There are dangers in humans of tropical ancestry trying to raise their vitamin d levels to Northern Europeans’ natural levels, let alone trying to attain the very high putative ‘optimums’ that are now close to being officially recommended for everbody and which only 3% of English people reach with normal sun exposure.

UNFORTUNATELY our norms for adequate vitamin intake are based on subjects or populations of European origin. We are thus diagnosing vitamin-D deficiency in non-European individuals who are, in fact, perfectly normal. This is particularly true for African Americans, nearly half of whom are classified as vitamin-D deficient, even though few show signs of calcium deficiency—which would be a logical outcome. Indeed, this population has less osteoporosis, fewer fractures, and a higher bone mineral density than do Euro-Americans, who generally produce and ingest more vitamin D .
[…]
By pathologizing non-Europeans as being vitamin-D deficient, modern medicine is paving the way for programs that are well intentioned but ultimately tragic in their consequences: mass vitamin-D supplementation to be dispensed through the school system and awareness campaigns. Such public health programs have already been proposed for African Americans and northern indigenous peoples.

What will be the outcome of raising vitamin-D levels in these populations? Keep in mind that we are really talking about a hormone, not a vitamin. This hormone interacts with the chromosomes and gradually shortens their telomeres if concentrations are either too low or too high. Tuohimaa (2009) argues that optimal levels may lie in the range of 40-60 nmol/L. In non-European populations the range is probably lower. It may also be narrower in those of tropical origin, since their bodies have not adapted to the wide seasonal variation of non-tropical humans.

If this optimal range is continually exceeded, the long-term effects may look like those of aging:”

“Ninety-one per cent of athletes were found to be deficient in 25(OH)D (serum concentration <20 ng/ml). Athletes with severe deficiencies were significantly younger than those with less marked deficiency. A subset of athletes underwent bone mineral density assessment and 59 % were shown to have at least one Z-score less than −1; despite this, however, no athletes reported a stress fracture. There was no correlation between 25(OH)D concentration and sunlight exposure, skin coverage and skin colouring"

“Among women, an increased rate of mortality was observed both for deficient concentrations and very high concentrations (>124nmol/L). Results suggest that caution should be exercised in using very high dose vitamin D supplementation in prevention trials that may result in high concentrations of vitamin D (>100nmol/L). Results suggest that caution should be exercised in using very high dose vitamin D supplementation in prevention trials that may result in high concentrations of vitamin D (>100nmol/L).”

“The increase in 25(OH)D level after UVB exposure was negatively correlated with baseline 25(OH)D level (P<0.001) and positively correlated with baseline total cholesterol level (P=0.005), but no significant correlations were found with constitutive or facultative skin pigmentation. In addition, we paired a dark-skinned group with a fair-skinned group according to baseline 25(OH)D levels and found no differences in 25(OH)D increase after identical UVB exposure."

This is ptetty convincing, high vitamin D levels are extemely dangerous for some populations.

“… positive associations exist between 25-hydroxyvitamin D and aorta and carotid artery CP in African-Americans. The effects of supplementing vitamin D to raise the serum 25-hydroxyvitamin D level on atherosclerosis in African-Americans are unknown. Prospective trials are needed to determine the cardiovascular effects of supplemental vitamin D in this ethnic group”